The overall goal of the proposed research is to investigate whether clinically normal older individuals with evidence of fibrillar amyloid deposition are in the prodromal phases of Alzheimer's disease. We will study 100 clinically normal individuals (CDR 0; MMSE 27-30; performance within <1.5 SD on age and education matched neuropsychological test norms) with PIB PET amyloid imaging to accomplish three specific aims: 1) To investigate the factors associated with high amyloid deposition in normals, including age, cognitive reserve, family history and genetic risk-factors for AD; 2) To investigate whether normals with high amyloid burden demonstrate abnormalities on functional and structural imaging measures, consistent with the alterations seen in prodromal AD; and 3) To determine if normals with high amyloid deposition are more likely to demonstrate clinical decline on sensitive measures of episodic memory and progress to a stage of mild cognitive impairment (MCI). Our preliminary data, as well as reports from other groups, suggest that a substantial proportion of clinically normal individuals have evidence of amyloid deposition on PIB PET imaging, in a pattern similar to that observed in clinical AD. Our preliminary data suggest that these normals with high amyloid deposition demonstrate functional and structural alterations in a specific set of brain regions, similar to the pattern of image abnormality commonly reported in MCI and AD. We hypothesize that higher levels of PIB retention will correlate with greater functional abnormality on functional MRI and FDG- PET imaging, as well as greater atrophy in medial temporal lobe and parietal cortices on volumetric MRI. Furthermore, we hypothesize that normals with high amyloid burden will manifest impairment on challenging episodic memory tests, and will demonstrate a higher likelihood of clinical decline towards MCI and ultimately clinical AD. This project will draw heavily on the resources of the MADRC, in particular, the Longitudinal Cohort of the Clinical Core, the Neuroimaging SubCore, and the Data/Statistics Core, as well as interface closely with the investigation of amyloid deposition in Projects 2 and 3. RELEVANCE (See instructions): The long presymptomatic phase of AD provides a critical opportunity for potential intervention with effective therapies. It is essential, however, to develop biological and imaging markers that will track disease progression in the presymptomatic phases and predict onset of clinical symptoms. This project will provide fundamental information on the relationship of amyloid deposition to brain dysfunction and clinical decline.